Process for preparing benzimidazole-type compounds

ABSTRACT

The present invention relates to an improved process for the preparation of proton pump inhibitors of the benzimidazole-type such as rabeprazole, omeprazole, pantoprazole, lansoprazole and esome prazole, of general formula (1) by oxidation of the corresponding sulfide followed by extraction of the sulfone by-product with an acqueous alkaline solution at controlled pH.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is the national stage of Application No.PCT/EP02/07693, filed Jul. 9, 2002, which application claims priorityfrom EPO Application No. 01202696.9, filed Jul. 16, 2001.

[0002] The present invention relates to an improved process for thepreparation of proton pump inhibitors of the benzimidazole-type such asrabeprazole, omeprazole, pantoprazole, lansoprazole and esomeprazole.

[0003] A benzimidazole-type compound or an alkali metal salt thereof hasa strong inhibitory action on the so-called proton pump. In a generalsense, they may be used for prevention and treatment of gastric-acidrelated diseases in mammals and especially in man, including e.g.gastro-oesophageal reflux, gastritis, duodenitis, gastric ulcer andduodenal ulcer.

[0004] Proton pump inhibitors of the benzimidazole-type are verysusceptible to degradation under acidic or neutral conditions andparticular reaction conditions are needed for their preparation.Processes for the preparation of said benzimidazole-type compounds havebeen disclosed, for instance, in EP-0,005,129, EP-0,066,287,EP-0,174,726, and EP-0,268,956.

[0005] The present invention provides an improved process for preparingbenzimidazole-type compounds of general formula (I)

[0006] wherein R¹ and R² are the same as or different from each otherand are selected from hydrogen, methoxy or difluoromethoxy, R³, R⁴ andR⁵ are the same as or different from each other and are selected fromhydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy,

[0007] characterized by the steps of

[0008] a) reacting a compound of general formula (II)

[0009]  with an oxidizing agent in a suitable solvent,

[0010] b) extracting the reaction mixture with an aqueous alkalinesolution with a pH ranging from 9.50 to 12.00 and removing the waterlayer,

[0011] c) extracting the organic layer of the previous step with anaqueous alkaline solution having a pH of 13.00 or higher and removingthe organic layer,

[0012] d) isolating the compound of formula (I) from the water layer ofthe previous step.

[0013] The term “proton pump inhibitors of the benzimidazole-type”,“benzimidazole-type compounds” or “compounds of formula (I)” is meant toinclude both the neutral form of said compounds and the alkaline saltforms of said compounds. Alkaline salts forms are for instance the Mg²⁺,Ca²⁺, Na⁺, K⁺ or Li⁺ salts, preferably the Mg²⁺ or Na⁺ salts. Whereapplicable, the benzimidazole-type compounds of formula (I) include theracemic form, or a substantially pure enantiomer thereof, or alkalinesalts of the single enantiomers.

[0014] The structural formulae of some of these proton pump inhibitorsof the benzimidazole-type are listed below:

[0015] Suitable proton pump inhibitors of the benzimidazole-type are forexample disclosed in EP-0,268,956, EP-0,005,129, EP-0,066,287, andEP-0,174,726. EP-0,652,872 discloses esomeprazole, i.e. the magnesiumsalt of the (−)-enantiomer of omeprazole.

[0016] Typically, benzimidazole-type compounds of formula (I) areprepared by oxidation of the sulfide intermediates of formula (II) in asuitable solvent.

[0017] The oxidation step uses an oxidizing agent such as,m-chloroperoxybenzoic acid, monoperoxyphthalate, hydrogen peroxide (withor without catalysts), permanganates, N-chloro or N-bromo succinimide,1,3-dibromo-5,5-dimethylhydantoin, 2-hydroperoxyhexafluoro-2-propanol,iodosylbenzene, manganese(III) acetylacetonate, oxygen (with or withoutcatalysts), ozone, peroxy monosulfate, ruthenium tetroxide, perborate,periodate, acyl nitrates, tert-butylhydroperoxide, dimethyl dioxiranes,hypochlorite, cerium ammonium nitrate, 2-nitrobenzenesulfinylchloride/potassium superoxide, N-sulfonyloxaziridines, sodium bromite,benzoyl peroxide and the like, in a solvent system consisting of anorganic solvent such as, e.g. dichloromethane.

[0018] Since proton pump inhibitors of the benzimidazole-type are verysusceptible to degradation under acidic or neutral conditions thereaction mixture is usually worked-up under basic conditions. Thesebasic conditions may decompose any unwanted oxidizing agent stillpresent in the reaction mixture and may also neutralise any acid formedwhen the oxidizing agent is consumed in the oxidation reaction.

[0019] The main problem with the oxidation reaction to convert thesulfide intermediates of formula (II) into the sulfoxide compounds offormula (I) is over-oxidation, i.e. oxidation from sulfoxides of formula(I) to sulfones of formula (III).

[0020] The formation of sulfones of formula (III) due to over-oxidationis almost impossible to avoid and can be kept to a minimum by performingthe oxidation reaction at a low temperature and restricting the amountof oxidizing agent. Typically the amount of oxidizing agent is less than1 molar equivalent of the starting material, i.e. sulfide intermediatesof formula (II), which inevitably results in a less than 100% conversionof starting material. Usually the amount of oxidizing agent is acompromise between maximum conversion of starting material, maximumformation of sulfoxides of formula (I) and minimum formation of unwantedsulfones of formula (III).

[0021] Furthermore removal of the sulfones of formula (III) has oftenproved to be difficult, time-consuming and costly, in particular whenhigh performance chromatography on an industrial scale is needed.

[0022] The object of the present invention is to provide an improvedmethod for the synthesis of benzimidazole-type compounds of formula (I),which is more convenient and more efficient than the previously knownmethods.

[0023] The present invention achieves this object by providing animproved process for preparing benzimidazole-type compounds of generalformula (I) which is characterized by the steps of

[0024] a) reacting a compound of general formula (II)

[0025]  with an oxidizing agent in a suitable solvent,

[0026] b) extracting the reaction mixture with an aqueous alkalinesolution with a pH ranging from 9.50 to 12.00 and removing the waterlayer,

[0027] c) extracting the organic layer of the previous step with anaqueous alkaline solution having a pH of 13.00 or higher and removingthe organic layer,

[0028] d) isolating the compound of formula (I) from the water layer ofthe previous step.

[0029] This improved process has the advantage that the first extractionstep b) removes any formed sulfones of formula (III) and the secondextraction step c) removes any unreacted sulfides of formula (II)whereby the water layer in step d) only contains the desiredbenzimidazole-type compounds of formula (I) which can be easily purifiedto the level required for pharmaceutical preparations.

[0030] A further advantage of the improved process is that higheramounts of oxidizing agent can be used, giving a higher yield of thedesired compounds of formula (I) and fewer unreacted sulfides of formula(II), since any formed undesired sulfones of formula (III) are easilyremoved by the first extraction step thereby making further purificationof the isolated sulfoxides of formula (I) much more easy.

[0031] The oxidizing agent used in the above described improved processcan be m-chloroperoxybenzoic acid, monoperoxyphthalate, hydrogenperoxide (with or without catalysts), permanganates, N-chloro or N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin,2-hydroperoxyhexafluoro-2-propanol, iodosylbenzene, manganese(III)acetylacetonate, oxygen (with or without catalysts), ozone, peroxymonosulfate, ruthenium tetroxide, perborate, periodate, acyl nitrates,tert-butylhydroperoxide, dimethyl dioxiranes, hypochlorite, ceriumammonium nitrate, 2-nitrobenzenesulfinyl chloride/potassium superoxide,N-sulfonyloxaziridines, sodium bromite, benzoyl peroxide or any otheroxidizing agent suitable for oxidising sulfides of formula (II).Preferably m-chloroperoxybenzoic acid is used. Said oxidizing agent issuitably used in an amount of 0.5 to 2.0 molar equivalents of startingmaterial, i.e. sulfides of formula (II). The optimal amount of oxidizingagent depends on the type of oxidizing agent used, the specific sulfideof formula (II) and further reaction conditions such as solvent andtemperature, and can easily be determined by the skilled person.

[0032] The aqueous alkaline solution in the first and second extractionstep can be any aqueous solution of an inorganic base, such as sodiumhydroxide, potassium hydroxide, sodium carbonate and the like; or anyaqueous solution of an organic base such as aqueous ammonia and thelike.

[0033] The pH of the first extraction step generally ranges from 9.50 to12.00 and preferably from 10.50 to 11.50. When the benzimidazole-typecompounds of formula (I) is rabeprazole the pH preferably ranges from10.70 to 11.20, more preferably the pH ranges from 10.85 to 10.95.

[0034] The compounds of formula (I) can be isolated from the water layerin step d) for instance by adding an organic solvent, such as, e.g.dichloromethane, to said water layer and lowering the pH whereby saidcompounds of formula (I) are transferred to the organic layer. Loweringthe pH can be done for instance by adding an aqueous ammonium acetatesolution. Concentrating said organic layer under vacuum then yields thedesired compounds of formula (I).

[0035] Particular benzimidazole-type compounds of formula (I) that canbe prepared by the improved process of the present invention arerabeprazole, omeprazole, pantoprazole, lansoprazole, and esomeprazole;in particular rabeprazole.

[0036] In another aspect, the present invention also provides a processfor removing sulfones of formula (III), wherein R¹ and R² are the sameas or different from each other and are selected from hydrogen, methoxyor difluoromethoxy, R³, R⁴ and R⁵ are the same as or different from eachother and are selected from hydrogen, methyl, methoxy, methoxypropoxy ortrifluoroethoxy,

[0037] from a reaction mixture comprising sulfoxides of formula (I),wherein R¹ and R² are the same as or different from each other and areselected from hydrogen, methoxy or difluoromethoxy, R³, R⁴ and R⁵ arethe same as or different from each other and are selected from hydrogen,methyl, methoxy, methoxypropoxy or trifluoroethoxy,

[0038] by extracting the reaction mixture with an aqueous alkalinesolution with a pH ranging from 9.50 to 12.00, preferably from 10.50 to11.50, and removing the water layer and isolating the sulfoxides offormula (I) from the organic layer.

[0039] When the sulfoxide of formula (I) is rabeprazole the pHpreferably ranges from 10.70 to 11.20, more preferably the pH rangesfrom 10.85 to 10.95.

[0040] A preferred embodiment of said process for removing sulfones offormula (III) is when the sulfoxide of formula (I) is rabeprazole.

[0041] The present invention is illustrated below with non-limitingexamples.

Experimental Part

[0042] In the procedures described hereinafter the followingabbreviations were used: “m-CPBA” stands for meta-chloroperoxybenzoicacid, “PTBI” stands for2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole,“PPSI” stands for2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(also known as rabeprazole), and “SUBI” stands for2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfonyl]-1H-benzimidazole.

EXAMPLE 1

[0043] To a solution of PTBI (0.25 mol) in dichloromethane (688 ml),stirred and kept at a temperature of −20° C., a solution of m-CPBA (0.22mol) in dichloromethane (330 ml) was added over 1 hour while keeping thetemperature of the reaction mixture at −20° C. The reaction mixture wasstirred at −20° C. for 30 minutes.

[0044] First Extraction Step

[0045] Water (368 ml) was added to the organic layer and the pH wasraised to 10.40 with a NaOH solution (10%). The pH of the reactionmixture was adjusted to pH=10.85 with an aqueous NH₃ solution and thewater layer was separated from the organic layer.

[0046] Second Extraction Step

[0047] Water (368 ml) was added to the organic layer and the pH wasraised to 13.0 with a NaOH solution (10%). The organic layer was removedand dichloromethane (168 ml) was added to the water layer. Whilestirring, an aqueous ammonium acetate solution was added to a pH of10.50. The water layer was removed from the organic layer and theorganic layer was concentrated under reduced pressure yielding aresidue. Said residue was crystallised from acetone, yielding PPSI(0.143 mol, 57%).

EXAMPLE 2

[0048] To a solution of PTBI (0.25 mol) in dichloromethane (688 ml),stirred and kept at a temperature of −20° C., a solution of m-CPBA (0.15mol) in dichloromethane (360 ml) was added over 1 hour while keeping thetemperature of the reaction mixture at −20° C. The reaction mixture wasstirred at −20° C. for 30 minutes.

[0049] Extraction Step

[0050] Water (368 ml) was added to the reaction mixture and the pH wasraised to 13.0 with a NaOH solution (10%). The organic layer was removedand dichloromethane (168 ml) was added to the water layer. Whilestirring, an aqueous ammonium acetate solution was added to a pH of10.50. The water layer was removed from the organic layer and theorganic layer was concentrated under reduced pressure yielding aresidue. Said residue was crystallised from acetone, yielding PPSI (0.11mol, 44%).

[0051] Purity of the obtained PPSI was measured using HPLC on aNucleosil 100 C18 (5 μm, 150 mm×4.6 mm I.D.) column using isocraticelution with a flow rate of 1 ml/minute, a mobile phase consisting of40% eluent A and 60% eluent B (eluent A is a mixture of 0.05 M KH₂PO₄and 0.05 M Na₂HPO₄ with a pH of 7 in a 2:1 (v/v) ratio; eluent B ismethanol) and UV detection at 290 nm. TABLE 1 comparison of reactionparameters (yield of PPSI is determined after crystallisation and isrelative to the starting material PTBI) mol equivalent of % ofside-product m-CPBA yield of PPSI (SUBI) Example 1 0.88 57% ≦0.8%Example 2 0.60 44% ≦0.8%

[0052] For use in pharmaceutical preparations PPSI, generally known asrabeprazole, should not contain more than 0.8% of the sulfone SUBI.Hence the use of the first extraction step which removes any formedsulfone from the reaction mixture allows for the use of a higher amountof oxidizing agent, thereby giving a substantially higher yield of PPSIwithout the need to change the work-up procedure, i.e. crystallisation,to obtain the sulfoxide PPSI containing 0.8% or less of the sulfoneSUBI.

EXAMPLE 3 General Oxidation and Extraction Procedure

[0053] A. Method A (with Additional Extraction Step for RemovingSulfones of Formula (III))

[0054] To a solution of a sulfide intermediate of formula (II) (0.05mol) in dichloromethane (137.5 ml), stirred and kept at a temperature of−40° C., a solution of m-CPBA (0.92 equivalents or 0.046 mol) indichloromethane (82.5 ml) was added over 1 hour while keeping thetemperature of the reaction mixture at −40° C. The reaction mixture wasstirred at −40° C. for 30 minutes.

[0055] First Extraction Step

[0056] Cooling of the reaction mixture was stopped before the pH wasraised to 10.40 with a NaOH solution (10%) and water (75 ml) was addedto the organic layer. The pH of the reaction mixture was adjusted topH=11.10 with an aqueous NH₃ solution and the water layer was separatedfrom the organic layer.

[0057] Second Extraction Step

[0058] Water (75 ml) was added to the organic layer of the previous stepand the pH was raised to 13.0 with a NaOH solution (10%). The organiclayer was removed and dichloromethane (75 ml) was added to the waterlayer. While stirring, an aqueous ammonium acetate solution was added toa pH of about 10.44. The water layer was removed from the organic layerand the organic layer was concentrated under reduced pressure yielding asolid residue.

[0059] B. Method B (without Additional Extraction Step for RemovingSulfones of Formula (III))

[0060] To a solution of a sulfide intermediate of formula (II) (0.05mol) in dichloromethane (137.5 ml), stirred and kept at a temperature of−40° C., a solution of m-CPBA (0.92 equivalents or 0.046 mol) indichloromethane (82.5 ml) was added over 1 hour while keeping thetemperature of the reaction mixture at −40° C. The reaction mixture wasstirred at −40° C. for 30 minutes.

[0061] Extraction Step

[0062] Cooling of the reaction mixture was stopped before the pH wasraised to 13.0 with a NaOH solution (10%) and water (75 ml) was added tothe organic layer. The organic layer was removed and dichloromethane (75ml) was added to the water layer. While stirring, an aqueous ammoniumacetate solution was added to a pH of 10.50. The water layer was removedfrom the organic layer and the organic layer was concentrated underreduced pressure yielding a solid residue.

[0063] C. Results

[0064] The following Table 3 lists the results for the proton pumpinhibitors rabeprazole, omeprazole and lansoprazole prepared both timesusing Method A (with additional extraction step for removing sulfones offormula (III)), and Method B (without additional extraction step forremoving sulfones of formula (III)).

[0065] Starting sulfide of formula (II) for the preparation ofrabeprazole was2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole.Starting sulfide of formula (II) for the preparation of omeprazole was5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole.Starting sulfide of formula (II) for the preraration of lansoprazole was2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole.

[0066] The amount of sulfones of formula (III) and compounds of formula(I) present in the obtained solid residues, prepared according to MethodA or Method B, was measured using HPLC on a Nucleosil 100 C18 (5 μm, 150mm×4.6 mm I.D.) column using isocratic elution with a flow rate of 1ml/minute, a mobile phase consisting of 40% eluent A and 60% eluent B(eluent A is a mixture of 0.05 M KH₂PO₄ and 0.05 M Na₂HPO₄ with a pH of7 in a 2:1 (v/v) ratio; eluent B is methanol) and UV detection at 290nm. Standard deviation is less than 5%. TABLE 3 amount of sulfones offormula (III) and compounds of formula (I) present in the obtained solidresidues Rabeprazole % sulfon in residue % rabeprazole in residue MethodA 0.33  92.5 Method B 0.78  90.4 Omeprazole % sulfon in residue %omeprazole in residue Method A 0.26  99.4 Method B 0.53 100.5Lansoprozole % sulfon in residue % lansoprazole in residue Method A 4.1 100.5 Method B 11.3   97.8

1. An process for preparing benzimidazole-type compounds of generalformula (I)

wherein R¹ and R² are the same as or different from each other and areselected from hydrogen, methoxy or difluoromethoxy, R³, R⁴ and R⁵ arethe same as or different from each other and are selected from hydrogen,methyl, methoxy, methoxypropoxy or trifluoroethoxy, characterized by thesteps of a) reacting a compound of general formula (II)

 with an oxidizing agent in a suitable solvent, b) extracting thereaction mixture with an aqueous alkaline solution with a pH rangingfrom 9.50 to 12.00 and removing the water layer, c) extracting theorganic layer of the previous step with an aqueous alkaline solutionhaving a pH of 13.0 or higher and removing the organic layer, d)isolating the compound of formula (I) from the water layer of theprevious step.
 2. A process as claimed in claim 1 wherein the pH of thefirst extraction step b) ranges from 10.50 to 11.50.
 3. A process asclaimed in claim 1 wherein the oxidizing agent is selected fromm-chloroperoxybenzoic acid, monoperoxyphthalate, hydrogen peroxide (withor without catalysts), permanganates, N-chloro or N-bromo succinimide,1,3-dibromo-5,5-dimethylhydantoin, 2-hydroperoxyhexafluoro-2-propanol,iodosylbenzene, manganese(III) acetylacetonate, oxygen (with or withoutcatalysts), ozone, peroxy monosulfate, ruthenium tetroxide, perborate,periodate, acyl nitrates, tert-butylhydroperoxide, dimethyl dioxiranes,hypochlorite, cerium ammonium nitrate, 2-nitrobenzenesulfinylchloride/potassium superoxide, N-sulfonyloxaziridines, sodium bromite,or benzoyl peroxide.
 4. A process as claimed in claim 3 wherein theoxidizing agent is m-chloroperoxybenzoic acid.
 5. A process as claimedin claim 1 wherein the benzimidazole-type compounds of formula (I) isselected from rabeprazole, omeprazole, pantoprazole, lansoprazole, andesomeprazole.
 6. A process as claimed in claim 5 wherein thebenzimidazole-type compounds of formula (I) is rabeprazole.
 7. A processas claimed in claim 6 wherein the pH of the first extraction step b)ranges from 10.70 to 11.20.
 8. A process for removing sulfones offormula (III), wherein R¹ and R² are the same as or different from eachother and are selected from hydrogen, methoxy or difluoromethoxy, R³, R⁴and R⁵ are the same as or different from each other and are selectedfrom hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy,

from a reaction mixture comprising sulfoxides of formula (I),

by extracting the reaction mixture with an aqueous alkaline solutionwith a pH ranging from 9.50 to 12.00, removing the water layer andisolating the sulfoxides of formula (I) from the organic layer.
 9. Aprocess as claimed in claim 8 wherein the pH of the extraction stepranges from 10.50 to 11.50.
 10. A process as claimed in claim 8 whereinthe sulfoxide of formula (I) is rabeprazole.
 11. A process as claimed inclaim 9 wherein the sulfoxide of formula (I) is rabeprazole.
 12. Aprocess as claimed in claim 6 wherein the pH of the first extractionstep b) ranges from 10.85 to 10.95.
 13. A process as claimed in claim 2wherein the oxidizing agent is selected from m-chloroperoxybenzoic acid,monoperoxyphthalate, hydrogen peroxide (with or without catalysts),permanganates, N-chloro or N-bromo succinimide,1,3-dibromo-5,5-dimethylhydantoin, 2-hydroperoxyhexafluoro-2-propanol,iodosylbenzene, manganese(III) acetylacetonate, oxygen (with or withoutcatalysts), ozone, peroxy monosulfate, ruthenium tetroxide, perborate,periodate, acyl nitrates, tert-butylhydroperoxide, dimethyl dioxiranes,hypochlorite, cerium ammonium nitrate, 2-nitrobenzenesulfinylchloride/potassium superoxide, N-sulfonyloxaziridines, sodium bromite,or benzoyl peroxide.
 14. A process as claimed in claim 13 wherein thebenzimidazole-type compounds of formula (I) is rabeprazole.